B-Cell Receptor (BCR) signaling is one of the central pathways involved in survival and proliferation of Chronic Lymphocytic Leukemia (CLL), Mantle cell lymphoma (MCL), and Diffuse large B-cell lymphoma (DLBCL) cells. Despite the major progress made over the past years for the treatment of these diseases, no cures are currently available for relapsed or refractory CLL or NHL outside of stem cell transplant indicating the need for novel therapeutic options. A critical component of the BCR pathway is Bruton's tyrosine kinase (BTK), a non- receptor tyrosine kinase in the Tec kinase family, which is expressed predominantly in B-lymphocytes. Ibrutinib, which binds and block BTK, has shown extremely promising results in CLL, MCL, and also a subset of DLBCL driven by BCR signaling. However, despite the impressive responses and durability of remissions with ibrutinib in CLL compared to other therapies, MRD-negative status has generally not been achieved. We have recently defined mutations of either BTK (C481) or PLC2 in ibrutinib resistance patients that could explain lack of ibrutinib efficacy in this subset of patients. Therefore the combination of new therapies with ibrutinib in CLL to increase frequency of MRD-negative remissions, and also in MCL and DLBCL to improve response rate/remission duration, represents a major therapeutic goal. These malignancies are also associated with aberrant activation of several survival pathways including PI3K/AKT, BTK, and NF-B that merge with tumor suppressor proteins exported by XPO1. Our previous published work has shown that XPO1 is a validated therapeutic target for CLL, and facilitated the translation of selinexor, a selective inhibitors of XPO1, from bench to clinic. We are completing a single agent phase I study of selinexor in advanced hematologic malignancies where anti-tumor activity has been observed in lymphoma, CLL, and acute myeloid leukemia. XPO1 has been shown to regulate expression of a subset of mRNAs by serving as an alternative exporter. Our data indicate that XPO1 exports mRNAs involved in CLL pathogenesis and progression (i.e. Tcl1 and Btk) and that selinexor prevents their export and translation. Additionally, selinexor treatment suppresses B-cell activation, proliferation and migration in CLL cells and is effective both in vitro and in vivo in ibrutinib resistant cells. Moving forth we believe that understanding of mRNA export mediated regulatory mechanisms is important for the successful design of clinically viable therapeutics to potentially achieve a cure for relapse/refractory CLL/SLL. Specifically, this proposal aims to improve our understanding of the role of XPO1 in the context of oncogenic signaling important for the pathogenesis and microenvironment homing of CLL, and proposes a Phase I trial of ibrutinib and selinexor combination therapy. We believe that this work will lead to a new combination that will be effective in CLL and NHL and may overcome single agent resistance mechanisms.